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Christine M. Lovly
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.15 - Real-world ALK Testing Trends and Patterns in Patients with Advanced NSCLC in the United States (ID 3333)
00:00 - 00:00 | Presenting Author(s): Christine M. Lovly
- Abstract
Introduction
Patients whose lung cancers harbor anaplastic lymphoma kinase (ALK) rearrangements are sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Several treatment guidelines recommend molecular testing to identify ALK-positive patients who are eligible for ALK TKI therapy. This study assessed real-world ALK testing patterns among community practices in the United States in patients with advanced non-small cell lung cancer (NSCLC) and explored treatments received prior to receiving test results in patients with ALK-positive NSCLC.
Methods
This retrospective analysis used data extracted from the Flatiron Health electronic health record-derived deidentified database. Patients ≥ 18 years old with a diagnosis of advanced NSCLC (clinical stage IIIB or IV as determined by pathologic and radiologic findings) and ≥ 2 clinic visits within the Flatiron Network between 01/01/2011 and 12/31/2019 were included.
Results
Overall, 60,025 patients with advanced NSCLC were identified, including 41,496 patients with non-squamous cell carcinoma and 15,291 patients with squamous cell carcinoma. Between 2011 and 2019, 36,691 (61.1%) patients with advanced NSCLC were ever tested for ALK by various diagnostic tests. Of these, 1,042 patients were ALK-positive. In patients with advanced NSCLC, ALK testing rates increased from 33.1% in 2011 to 73.0% in 2019. Considering histological subtype, ALK testing rates increased from 41.6% in 2011 to 81.6% in 2019 in patients with non-squamous cell carcinoma and from 13.6% in 2011 to 50.4% in 2019 in patients with squamous cell carcinoma. The proportion of ALK testing conducted by fluorescence in situ hybridization (FISH) declined from 68.3% in 2011 to 32.1% in 2019, while the use of next-generation sequencing (NGS) increased from < 1% in 2011 to 52.2% in 2019. Overall, tissue samples were most commonly used for testing (85.1%), followed by blood samples (13.5%), and the use of blood samples for ‘liquid biopsy’ increased from < 1% in 2011 to 28.2% in 2019. Among 983 patients who tested ALK-positive with a non-missing test result date, 24.7% of patients initiated therapy before receiving their first ALK-positive test results, with immuno-oncology (IO) therapies the most common treatments initiated since 2017. Among those who tested ALK-positive, the proportion of patients who started IO therapies before receiving ALK test results increased from 4.8% in 2016 to 17.8% in 2019. Median time from diagnosis of advanced NSCLC to first ALK-positive result date was 23 days. This included a laboratory turnaround time of 9 days from the date specimens were received by the laboratory to the test report date.
Conclusion
Over time, ALK testing rates have increased, reaching over 70.0% since 2017. There was increased use of NGS and a concurrent decrease in the use of FISH as the primary testing method. Despite this increase, over a quarter of patients with advanced NSCLC were not tested for ALK, indicating that many patients are not receiving recommended biomarker testing. Furthermore, 24.7% of patients who tested ALK-positive initiated therapy before receipt of ALK test results, which indicates that treatment decisions are sometimes being made in the absence of recommended biomarker data.
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.06 - Multicenter Analysis of Mechanisms of Resistance to Osimertinib (O) in EGFR Mutated NSCLC: An ATOMIC Registry Study (ID 1287)
00:00 - 00:00 | Author(s): Christine M. Lovly
- Abstract
- Presentation
Introduction
O is highly active in EGFR mutated NSCLC, but resistance is nearly inevitable. Oncologists can now perform serial blood or tumor molecular testing on such patients. A few single center series have documented a heterogeneous list of mechanisms of resistance to O in the 1st or later lines of therapy, but these have been limited by sample size. A consortium of cancer centers, such as The Academic Thoracic Oncology Medical Investigator’s Consortium (ATOMIC), is uniquely poised to combine patient populations and describe baseline and on treatment molecular features associated with benefit or resistance.
Methods
We created a database and secure web portal whereby investigators at sites throughout ATOMIC could enter comprehensive deidentified clinical, molecular, treatment and radiographic information on patients with metastatic EGFR mutated NSCLC, under IRB approval. All patients were eligible for inclusion, regardless of diagnosis date. Patients who received first line O (1L) and later line O (2+L) were included. For the purposes of this analysis, we evaluated all tissue and plasma samples obtained from the time of O was initiated until 45 days after stopping O. To evaluate for loss of alterations such as T790, we also assessed samples obtained prior to O treatment.
Results
We identified 799 patients across 12 sites in the United States and Canada who had been treated with O. In our cohort, median age at diagnosis was 63 (range 30-95), 541 (67.7%) were female, 429 (53%) were Caucasian, 753 (94.2%) presented with adenocarcinoma, and 314 (39.3%) received 1L O. Out of the 799 patients, 337 tissue samples and 176 plasma/urine samples were obtained after starting O, from which we have detailed molecular data on 161 and 170 samples, respectively from 162 patients. The columns in the table describe the patients for whom we have detailed molecular data, identify the proportion of these alterations only seen after O, the alterations identified in tissue/plasma, and the alterations seen with 1L/2+L O.
ConclusionMolecular Alteration
Overall,
n=162
Seen only
after
OIn Tissue,
n=94
In Plasma/ Urine,
n=87
1L O,
n=35
2+L O, n=126
#
%
#
#
%
#
%
#
%
#
%
T790 Loss
64
39.5
64
34
36.2
32
36.8
2
5.7
62
49.2
EGFR Amplification
29
17.9
8
12
12.8
21
24.1
6
17.1
22
17.5
CDKN2A/B Mutation/Loss
29
17.9
10
10
10.6
10
11.5
9
25.7
19
15.1
PIK3CA Mutation
27
16.7
15
15
15.9
15
17.2
6
17.1
21
16.7
MET Amplification
24
14.8
18
16
17
9
10.3
5
14.3
17
13.5
EGFR C797 S
18
11.1
18
11
11.7
11
12.6
2
5.7
16
12.7
KRAS Mutation
17
10.5
12
6
6.4
11
12.6
6
17.1
5
4
BRAF Mutation/ Amplification
13
8
5
7
7.4
8
9.2
2
5.7
11
8.7
PIK3CA Amplification
7
4.3
0
1
1.1
6
6.9
2
5.7
5
4
MET Mutation
7
4.3
3
2
2.1
7
8
1
2.9
6
4.8
KRAS Amplification
7
4.3
4
3
3.2
4
4.6
2
5.7
5
4
FGFR2 Mutation
6
3.7
0
2
2.1
4
4.6
1
2.9
5
4
Rearrangements/ Fusions (in ALK, BRAF, FGFR3, NTRK1, and RET)
5
3.1
5
4
4.3
2
2.3
0
0
5
4
FGFR1 Mutation
5
3.1
3
3
3.2
2
2.3
1
2.9
4
3.2
FGFR3 Mutation
4
2.5
2
4
4.3
1
1.1
0
0
4
3.2
FGFR4 Mutation
3
1.9
1
3
3.2
0
0
0
0
2
1.6
EGFR G724S
3
1.9
3
2
2.1
1
1.1
0
0
3
2.4
EGFR L718Q/V
2
1.2
2
0
0
2
2.3
1
2.9
1
0.8
In the largest analysis of mechanisms of resistance to O performed to date, we found that potential mediators of resistance were heterogeneous, including PIK3CA, MET, BRAF, CDKN2A/B and FGFR1-4, in addition to alterations within EGFR itself. Abstraction was completed in mid-August (final total 1186 EGFR mutated patients), so we expect numbers to increase in our final analysis. At the time of presentation, we will share information on histologic transformations, specific alterations seen, co-mutation status and survival as a function of mechanisms of resistance and line of therapy.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.41 - Detection of Diverse EGFR c-terminal Truncations (C-trunc) and Sensitivity to Tyrosine Kinase Inhibitors (TKIs) in the Clinic (ID 1839)
00:00 - 00:00 | Presenting Author(s): Christine M. Lovly
- Abstract
Introduction
EGFR kinase domain (KD) mutations are classic targetable drivers in non-small cell lung cancer (NSCLC) linked to approved TKIs. EGFR C-truncs are also found in human tumors and known to be activating in vitro. We aimed to describe the therapeutic implications of these C-trunc variants and hypothesized that they are targetable drivers in the clinic.
Methods
The Foundation Medicine (FM) genomic database (FMGD) of patients having undergone hybrid capture-based comprehensive genomic profiling (CGP) of tumor tissue or circulating tumor DNA (ctDNA) was interrogated to assess the prevalence of EGFR C-truncs affecting exons 25-28 and co-occurring known oncogenic drivers. All exons of EGFR were baited for tissue and ctDNA whereas introns 24-27 were baited for in tissue only.
A second database, the Flatiron Health (FH)-FM NSCLC Clinico-Genomic Database (CGDB), was explored to identify patients with advanced NSCLC (aNSCLC) whose tumors harbor EGFR C-truncs. CGDB is a nationwide (US-based) de-identified EHR-derived database, and includes patients in FMGD who also received care within the FH network. Clinical characteristics, treatment selections and response assessments were described for patients with aNSCLC diagnosed between 1/2011-9/2019.
Results
In the FMGD, EGFR C-truncs were detected in 0.27% (165/60,261) of aNSCLC cases, resulting from either rearrangements (70%) or mutations (nonsense, 14%; splice site, 8.9%; frameshift, 7.1%) affecting exons 25-28. EGFR C-truncs were detected in 0.28% and 0.21% of NSCLC tissue and ctDNA samples, respectively, with rearrangements with intronic breakpoints detected in 0.15% of tissue and 0.07% of ctDNA cases. Co-occurring EGFR KD mutations or other known drivers (primarily KRAS mutations and MET amplification) were detected with EGFR C-truncs in 29% and 11% of tissue and 38% and 19% of ctDNA cases, respectively.
In the CGDB, EGFR C-truncs were present in 0.36% (25/6,687) of samples from aNSCLC patients. Of these, 14 had documented receipt of EGFR TKI(s) and 12/14 (5 mutations, 7 rearrangements) had evaluable outcomes, including 6 with co-occurring EGFR driver mutations (4 exon 19 deletion, 2 L858R), 1 with BRAF V600E, and 1 with KRAS G12C. Of those with co-EGFR drivers, all had partial (PR) or complete responses to erlotinib (n=1, 12.2 months), afatinib (n=1, 18.2 months) or erlotinib followed by osimertinib (n=4, 8.0-42.4 months total). Of 4 evaluable cases with no co-occurring known drivers, 3 had EGFR TKI post CGP including 2 with PRs (EGFR Q1174*, osimertinib 5 months, ongoing; and EGFR exon 25 rearrangement, erlotinib followed by osimertinib, total 28 months) and 1 with progressive disease (EGFR exon 27 rearrangement, erlotinib 3 months). The fourth evaluable patient with EGFR C-trunc alone received erlotinib followed by osimertinib for 25 months total with a PR, then CGP 3 months prior to osimertinib discontinuation revealed an EGFR exon 25 splice site mutation.
Conclusion
EGFR C-truncs are detectable in NSCLC tissue and plasma using broad hybrid-capture based genomic profiling and may occur alone or with other EGFR activating mutations. Consistent with our hypothesis, preliminary real-world clinical data suggest that patients with these alterations may derive benefit from approved EGFR TKIs and additional studies are warranted.
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PDSC01 - Product Showcase (ID 294)
- Event: WCLC 2020
- Type: Product Showcases
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, Product Theater (via Industry Hub)
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PDSC01.01 - 360° Perspectives on Biomarker Testing in Non-Small Cell Lung Cancer by PFIZER (ID 4389)
00:00 - 00:00 | Author(s): Christine M. Lovly
- Abstract
Abstract not provided
